Peripheral Arterial Interventions Evolving Therapeutic

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I dedicate this book to:
To my wife Gail Shammas for her relentless
support and endless love and dedication to
her family, to my late father Wahib Shammas
who instilled in me discipline and hard work,
to my mom Vera Shammas for all her
continued sacrifices and love to her family,
to my daughter Anna Shammas who makes
me laugh and for her pure sweetness, to my
sons W John Shammas and Andrew Shammas
for their kindness, wonderful hearts, and
love to their family, to my siblings Robert,
Claudette, and Diana for being there for me
when I needed them, and to my patients for
being the source of my passion to research,
education, and clinical cardiology.
Preface

Peripheral arterial disease (PAD) is a universal problem affecting 10–15% of the

general population and is particularly prevalent with age. PAD is a marker for higher
cardiovascular events and mortality. A broader approach to treat these patients is of
paramount importance to reduce the morbidity and mortality of patients with this
disease. There has been a shift in the PAD treatment from a focus on revasculariza-
tion to implementing aggressive preventative therapies and improving the quality of
life of these patients. Pharmacologic and structured exercise interventions are now
first steps to improve the symptoms of patients with claudication. Revascularization
is typically reserved for claudicants that fail medical therapy, and for patients with
advanced limb ischemia with rest pain or ulcerations. Chronic limb-threatening
ischemia (CLTI) needs to be addressed aggressively with simultaneous preventa-
tive, pharmacologic, and revascularization strategies to reduce its burden of amputa-
tion and mortality. Smoking, diabetes, and chronic kidney disease are major risk
factors that need to be addressed and controlled. Several pharmacologic interven-
tions including antiplatelets, statins or PCSK-9 inhibitors, low dose rivaroxaban,
SGLT2 inhibitors, and others are now available for the endovascular specialist to
treat the PAD patient.
The endovascular treatment of peripheral arterial disease has gained momentum
and surpassed surgical therapies. Since early endovascular treatment of PAD with
balloon angioplasty, multiple newer therapies have emerged including second-­
generation self-expanding stents, atherectomy devices, specialty balloons and wires,
drug-coated balloons and drug-eluting stents, and crossing catheters and devices.
The strategy to leave the least metal behind has gained momentum particularly in
traditional no-stent zones such as the common femoral and popliteal arteries,
younger patients, in-stent restenosis, long and complex disease, and vessels below
the knee. An optimal strategy to treat infrainguinal arterial disease with the least
metal behind focuses on vessel prepping to gain the maximum minimal luminal area
without disruption of the deeper layers of the vessel, protecting the distal vascular
bed, and applying antiproliferative therapy to reduce restenosis. Although stenting
is endorsed by the guidelines, and in the short- and intermediate term provides good
outcomes, loss of patency is evident in the long term along with stent fractures and

vii
viii Preface

thrombosis. Carpet stenting becomes a real problem in the long term with a progres-
sive disease that requires multiple recurrent treatments. The least stent approach
allows overall excellent results with the combination of vessel prepping and drug-­
eluting balloons while keeping the doors opened for future therapies, a particularly
important strategy in younger patients. Randomized trials have not compared best-­
stent strategy to a no-stent strategy of vessel prepping and antiproliferative therapy.
In this book, we review peripheral arterial atherogenesis with a focus on risk fac-
tors and the global nature of atherosclerotic disease. Exercise and pharmacologic
therapies are then discussed followed by a review of strategies and devices and how
to approach different plaque morphologies in various vascular beds. Well-powered
randomized trials are unfortunately scarce in the field of PAD treatment. However,
world experts have been assembled in this book to fill in some of the gaps on how
to approach various PAD treatments. The last chapter puts it all together to provide
operators an optimal strategy for peripheral arterial interventions.
I am grateful to the many people who have contributed to this book and to the
excellent team at Springer for agreeing to publish it. This book is the culmination of
efforts by many experts dedicated to improve and prolong the lives of PAD patients.
A special thanks to our patients who voluntarily and willingly participated in the
many clinical trials that led to advancing this field. For them, we are forever
indebted. Furthermore, I could have not done this book without my wonderful wife,
Gail Shammas, for her relentless dedication to our research program, and her over-
whelming unconditional love and support to me and my family. Finally, I am also
grateful to our children W John, Andrew Nicolas, and Anna Elizabeth for appreciat-
ing and understanding the need to be away from them for long hours and days, and
to the entire Midwest Cardiovascular Research Foundation staff for being there for
me when I needed them. I do hope you will enjoy and make good use of this book.
This book is not intended to give medical advice or be a substitute to the medical
advice or a substitute to the medical judgment and decisions of endovascular spe-
cialists and other providers.

Davenport, IA, USA Nicolas W. Shammas

Contents

1 Peripheral Arterial Atherogenesis����������������������������������������������������������    1

Joseph M. Meyer, Thorsten M. Leucker, Steven R. Jones,
Seth S. Martin, and Peter P. Toth
2 
Risk Factors of Patients with Peripheral Arterial Disease ������������������   49
Michael J. Gimbel III
3 
The Role of Exercise in Treating Symptomatic Claudication
in Patients with Peripheral Arterial Disease������������������������������������������   61
Nicolas W. Shammas
4 
Pharmacologic Interventions in Patients with Peripheral
Arterial Disease����������������������������������������������������������������������������������������   67
Qais Radaideh and Nicolas W. Shammas
5 
Blood Vessel Compliance, Barotrauma and Angioplasty-Induced
Dissection Following Treatment of the Patient with Peripheral
Artery Disease������������������������������������������������������������������������������������������   81
Alexandra Stathis, Michiel T. Voûte, and Ramon L. Varcoe
6 
Controlling Dissections in Peripheral Arterial Interventions��������������   97
Nicolas W. Shammas
7 
The Role of Atherectomy in Vessel Prepping During
Infrainguinal Arterial Interventions������������������������������������������������������ 109
Andrew N. Shammas and Nicolas W. Shammas
8 
Vessel Preparation with Longitudinal and Controlled-Depth
Micro-Incisions���������������������������������������������������������������������������������������� 123
John P. Pigott
9 
Intravascular Lithotripsy for Calcified Peripheral
Arterial Disease���������������������������������������������������������������������������������������� 137
Ari J. Mintz and Peter A. Soukas

ix
x Contents

10 
Preserving Vessel Integrity and Reducing Vascular Recoil
with Focal Force Balloons ���������������������������������������������������������������������� 195
Effie K. Lambrinos, Edward D. Tubberville, Vinayak Subramanian,
and George L. Adams
11 
Reducing the Metal Burden in the Infrainguinal Arteries:
Tack Endovascular System���������������������������������������������������������������������� 209
Marianne Brodmann
12 
Drug-Coated Balloons in Infrainguinal Arteries���������������������������������� 217
Sriya A. Avadhani, Serdar Farhan, and Prakash Krishnan
13 
Stenting in Infrainguinal Interventions ������������������������������������������������ 245
Steve Henao
14 Femoropopliteal Chronic Total Occlusions: Approach
and Considerations for Crossing and Intervention������������������������������ 253
Michael H. Vu and Subhash Banerjee
15 
Approach to Treatment of Iliac Artery Disease������������������������������������ 271
Razan Elsayed and Beau M. Hawkins
16 
Chronic Limb-Threatening Ischemia: Evaluation
and Management�������������������������������������������������������������������������������������� 281
Timir K. Paul and Subhash Banerjee
17 
Distal Embolization in the Treatment of Peripheral
Arterial Disease���������������������������������������������������������������������������������������� 295
Michael H. Wholey
18 Management of Aortic Aneurysms �������������������������������������������������������� 309
Mel J. Sharafuddin and Jeanette H. Man
19  utting It All Together: An Algorithmic Approach to Treat
P
Patients with Peripheral Arterial Disease���������������������������������������������� 319
Nicolas W. Shammas

Index������������������������������������������������������������������������������������������������������������������ 329
About the Editor

Nicolas Shammas, MD, EJD, MS, FACC, FSCAI,

FSVM is the Founder and Research Director of the
Midwest Cardiovascular Research Foundation, Iowa,
USA. He is also the Medical Director of Cardiology
Services at Trinity Bettendorf Hospital and an Adjunct
Clinical Associate Professor of Medicine at the
University of Iowa Hospitals. Dr. Shammas is also an
Interventional Cardiologist at Cardiovascular
Medicine, LLC in Davenport, Iowa. He attended the
American University of Beirut in Beirut, Lebanon, for
his MD and MS in cardiac physiology combined pro-
gram. Dr. Shammas completed both a residency pro-
gram and postgraduate training in Interventional
Cardiology at the University of Iowa Hospitals and
General Cardiology training at the University of
Rochester Medical Center in Rochester, New York. Dr.
Shammas is board certified in Internal Medicine,
Cardiology, Endovascular Medicine, and Interventional
Cardiology. Dr. Shammas has published over 425 man-
uscripts, abstracts, book chapters, and books and par-
ticipated in over 220 national clinical trials. He was the
immediate past Governor of the American College of
Cardiology, Iowa Chapter.

xi
Chapter 1
Peripheral Arterial Atherogenesis

Joseph M. Meyer, Thorsten M. Leucker, Steven R. Jones, Seth S. Martin,

and Peter P. Toth

Peripheral Artery Disease

The terms describing the diseases of peripheral arteries are not uniformly used [1–
3]. In general, peripheral arterial disease is atherosclerosis of the vertebral, carotid,
mesenteric, and renal arteries and arteries of the upper and lower extremities.
Peripheral artery disease (PAD) technically refers to atherosclerosis in the upper
and lower extremities [4]. However, atherosclerosis of the lower extremities is more
common and more often symptomatic and thus will be the focus of this chapter [5].
Atherosclerosis of the upper extremities most commonly involves the brachioce-
phalic trunk and subclavian and axillary arteries [1]. The clinical spectrum of PAD
ranges from asymptomatic to critical limb ischemia (CLI) with limb loss (Table 1.1).
CLI is due to chronic ischemia with ankle pressures usually ≤50 mmHg and is
defined by rest pain or gangrene [6]. Chronic PAD severity is staged by the Fontaine
or Rutherford classifications (Table 1.2). Non-atherosclerotic processes, such as
external compression, vasculitis, or embolism, may mimic the signs and symptoms
of PAD, but are separate entities of peripheral arterial disease and will not be
addressed in this chapter.

J. M. Meyer · T. M. Leucker · S. R. Jones · S. S. Martin

Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University
School of Medicine, Baltimore, MD, USA
e-mail: [email protected]; [email protected]; [email protected]; [email protected]
P. P. Toth (*)
Ciccarone Center for the Prevention of Cardiovascular Disease, Johns Hopkins University
School of Medicine, Baltimore, MD, USA
CGH Medical Center, Sterling, IL, USA
e-mail: [email protected]

© The Author(s), under exclusive license to Springer Nature Switzerland AG 2022 1

N. W. Shammas (ed.), Peripheral Arterial Interventions, Contemporary
Cardiology, https://doi.org/10.1007/978-3-031-09741-6_1
2 J. M. Meyer et al.

Table 1.1 Common terms to describe the symptoms of peripheral artery disease
Hemodynamics Limb symptoms Function
Asymptomatic Abnormal ABI at rest or None recognized Limited date available, but
PAD after exercisea or other reduced walking endurance
objective evidence of and slower walking velocity
PAD (duplex ultrasound, have been documented; rate
computed tomographic of decline in walking
angiography, magnetic performance is at least as
resonance angiography) great as for patients with
intermittent claudication
Atypical Abnormal ABI at rest or Leg pain on exertion Limited walking distance
claudication after exercise that is not consistent and exercise performance
with classic due to PAD may be present;
“claudication”; may symptoms may or may not
include calf, thigh, or be reproducible on a daily
buttock basics as for classic
claudication
Claudication Abnormal ABI at rest or Reproducible Limited walking distance,
after exercise lower-extremity exercise performance due to
muscle fatigue or PAD
discomfort on
exertion, relieved by
rest within 10 min
Critical limb Hemodynamics evidence Distal leg pain at Very limited, usually
ischemia of severe PAD rest, with or without ambulatory only for short
ischemic ulcers or distance
gangrene
Acute limb Hemodynamics evidence Acute limb pain, Very limited as above
ischemia of severe PAD neurological
dysfunction
Additional
terms
Nonvascular Normal leg Typical or atypical May be caused by
claudication hemodynamics at rest and limb discomfort with rheumatologic or
with exercise effort neuromuscular disease
ABI ankle–brachial index
Table from Hiatt [4]
a
An abnormal ABI has previously been defined as <0.90, but recent evidence suggests that an ABI
<1.00 is indicative of PAD and an increased risk of systemic atherosclerotic events. In the presence
of diabetes mellitus, pressure measurements may be unreliable in some patients

PAD is traditionally defined by the resting ankle brachial pressure index (ABI)
<0.9, which is the ratio of ankle blood pressure to brachial artery blood pressure. If
abnormal, segmental blood pressure measurements of the lower extremity may be
performed to localize the stenosis. On physical exam, PAD may manifest as dimin-
ished or absent distal pulses, a femoral bruit, or discoloration of the lower extremity,
particularly pallor with elevation or dependent rubor. Other means to diagnose PAD
include the toe-brachial index (TBI), tissue oxygen pressure (TcPO2), and skin per-
fusion pressure, which may be particularly useful when clinical suspicion is high
despite a normal ABI, or when ABI >1.4, which suggests the artery is non-­
compressible secondary to extensive calcification.
1 Peripheral Arterial Atherogenesis 3

Table 1.2 Peripheral artery disease severity described by the Fontaine and Rutherford
classifications
Stages of peripheral artery disease
Fontaine classification
Stage I Asymptomatic
Stage II Intermittent claudication without rest
pain
IIa Claudication walking >200 m
IIb Claudication walking <200 m
Stage III Nocturnal pain or pain at rest
Stage IV Tissue loss (ulcers or gangrene)
Rutherford classification
Grade 0 Category 0 Asymptomatic
Grade I Category 1 Mild claudication
Category 2 Moderate claudication
Category 3 Severe claudication
Grade II Category 4 Ischemic rest pain
Grade III Category 5 Minor tissue loss
Category 6 Major tissue loss
Adapted from Aboyans [1]

Epidemiology and Risk Factors

PAD is a common disease with growing worldwide prevalence, particularly in low-

and middle-income countries (LMIC). Globally, an estimated 236.6 million people,
or 5.6% of the population aged 25 or older, are living with PAD as of 2015, an
increase from 202 million in 2010 [7, 8]. Between 2010 and 2015, the rise in PAD
was mostly observed in LMIC, where the prevalence rose over 22% compared to a
4.5% rise in high-income countries (HIC) [7].
The prevalence of PAD increases with age, particularly in HIC where the odds of
PAD increased 65% for each decade of life over age 25 years [7]. PAD steadily rises
after age 50, with a prevalence of 5.7% in patients aged 50–54, 9.1% in patients
aged 60–64, 14.1% in patients aged 70–74, 21.2% in patients aged 80–84, and
31.3% in patients aged 90 and older (Fig. 1.1). As the share of the US population
above age 65 is expected to continue to rise, the total burden of PAD is also expected
to rise [9]. In LMIC, factors such as rising pollution, sedentary lifestyle, psychologi-
cal stressors, and adoption of the Western diet may explain the recent rise of PAD in
these countries, which is expected to continue increasing [3]. In the USA, it is esti-
mated that approximately 30% of African American men and 27.6% of African
American women will develop PAD by the age of 80, compared to an estimated
19% of white men and women and 22% of Hispanic men and women [10]. This
racial difference remains even after adjusting for traditional risk factors [10], and
socioeconomic factors that limit access to healthcare and risk factor modification
likely account for some of this disparity [11].
4 J. M. Meyer et al.

HICs (male) LMICs (male)

0.5 Sample size (n)
8−500
0.4 501−2000
2001−5000
Prevalence

0.3
>5000
0.2

0.1

HICs (female) LMICs (female)

0.5

0.4
Prevalence

0.3

0.2

0.1

0
30 40 50 60 70 80 90 30 40 50 60 70 80 90
Age (years) Age (years)

Fig. 1.1 Prevalence of peripheral artery disease in high-income countries (HIC) and low- to
medium-income countries (LMIC) by sex. Prevalence rises with age for men and women. (Figure
from Song [7]. This is an open-access article distributed under the terms of the Creative Commons
CC-BY license, which permits unrestricted use, distribution, and reproduction in any medium,
provided the original work is properly cited. You are not required to obtain permission to reuse this
article)

Other significant risk factors for PAD include a history of cigarette smoking and
diabetes [12]. Hypertension, dyslipidemia, concomitant cardiovascular disease
(CVD), and renal dysfunction are also associated with PAD (Table 1.3) [7, 10].
While early studies recognized male sex as a risk factor, a more contemporary sam-
ple suggests that women <65 years of age are 24% more likely to have PAD (ABI
<0.9) compared to men, a finding that was attenuated but remained even in older age
[10]. A meta-analysis of worldwide population data showed men were 26% less
likely to have PAD than women after adjustment for risk factors, including age by
decade, driven primarily by women in LMIC despite these women having lower
prevalence of current smoking, hypertension, and diabetes [7]. In the Reduction of
1 Peripheral Arterial Atherogenesis 5

Table 1.3 Risk of peripheral artery disease for common risk factors, expressed as odds ratios (OR)

Risk factor OR (95% CI)

Age (per 10-year increase) 1.55 (1.38–1.75)
Male sex 0.74 (0.61–0.91)
Current smoker 2.82 (2.0–3.98)
Former smoker 1.70 (1.39–2.09)
Hypertension 1.67 (1.50–1.86)
Diabetes 1.89 (1.68–2.13)
Hypercholesterolemia 1.34 (1.17–1.53)
Cardiovascular disease 2.31 (1.89–2.83)
Obesity 0.96 (0.82–1.13)
Renal impairmenta 1.79 (1.03–3.12)
Data are from pooled observational studies of worldwide populations
Adapted from Song [7]
a
High-income countries only

Atherothrombosis for Continued Health (REACH) registry, a large, diverse sample

of outpatients with established CVD (coronary, cerebrovascular, or peripheral)
showed these atherosclerotic diseases have a broad overlap of risk factors, yet only
one in six patients had symptomatic polyvascular disease (disease of two or more
vascular territories). [13] This finding suggests that while atherosclerosis is a sys-
temic disease, risk factor exposure affects individual patients differently. While there
is significant overlap in risk factors in ASCVD, cigarette smoking and diabetes are
strongly linked to PAD [14]. Observational data suggest that current smokers have a
two- to threefold increase in risk of developing PAD [3, 7]. Patients with diabetes are
particularly at risk for severe complications of PAD, namely, due to reduced recogni-
tion of wounds due to diabetic neuropathy and poor wound healing [15].
The clinical phenotype of PAD also varies depending on the presence of risk fac-
tors. Among consecutive patients undergoing endovascular therapy for PAD
(Fontaine Stages II–IV), the distribution of PAD was classified as iliac (proximal),
femoropopliteal, or crural (distal) [14]. As depicted in Fig. 1.2 with the reference
comparator of femoropopliteal disease, current smoking and hypercholesterolemia
are associated with proximal disease, whereas age and diabetes are more highly
associated with distal disease. Hypertension has a relatively uniform impact on all
vascular territories, and male sex is more prevalent in proximal and distal disease.
Similar results were found in a large sample of outpatients referred for PAD evalu-
ation, which re-demonstrated proximal and distal phenotypes of PAD linked to spe-
cific risk factors: smoking, hypertension, and dyslipidemia associated with proximal
disease and older age, male sex, and diabetes associated with distal disease [16].
However, it is not currently possible to accurately prognosticate outcomes based on
disease location, likely due to the heterogeneous nature of PAD and differing clini-
cal status of selected patients [16, 17].
The presence and severity of PAD are associated with increased morbidity and
mortality [18–27]. Regardless of the presence of symptoms, patients with PAD are
6 J. M. Meyer et al.

Age Male Diabetes Hyper- Hyperchole- Current

gender mellitus tension sterolemia smoking

Iliac

Femoro-
popliteal

Crural

Fig. 1.2 Association of risk factors to the distribution of target lesions in a group of patients with
endovascular intervention for peripheral artery disease. Disease was classified as iliac (proximal),
femoropopliteal, or crural (distal), and wider and darker shading represents increase prevalence for
a given risk factor. (Figure from Diehm [14])

less active, have reduced functional capacity, and have reduced quality of life [18,
19]. The incidence of all-cause mortality was 19% after 5 years in patients with
asymptomatic PAD, which was nearly 50% higher than healthy controls.
Furthermore, the risk of disease progression from asymptomatic PAD to intermit-
tent claudication (IC) was 7% and IC to critical limb ischemia was 21% after 5 years
[20, 21]. Perhaps predictably, all-cause mortality in symptomatic patients was even
higher, occurring in 27% of patients after 5 years with a 2.8-fold higher rate of CV
mortality compared to healthy controls [20]. The risk of CV and all-cause mortality
increases as the ABI becomes progressively more abnormal (either <0.9 or >1.4)
[22], and the addition of ABI improves risk prediction when combined with the
Framingham risk score [23]. Among symptomatic patients with PAD in the
Examining Use of Ticagrelor in Peripheral Artery Disease (EUCLID) trial, 10.7%
of patients experienced CV death, myocardial infarction, or ischemic stroke; 1.7%
of patients were hospitalized for acute limb ischemia; and 12.5% underwent lower
extremity revascularization over a 30-month follow-up period [24]. The French
COhorte de Patients ARTériopathes (COPART) registry followed 940 hospitalized
patients with PAD. The risk of mortality and amputation increased with severity of
symptoms, ranging from IC to rest pain, and ultimately tissue loss. In patients with
tissue loss, mortality was highest at 28.7%, and the rate of amputation was 24.2% at
1 year [25]. More than half of amputees require contralateral amputation within
3 years, and mortality was as high as 50% at 5 years after first amputation [26]. In a
population study in Germany, the risk of CV events, amputation, or mortality
increased significantly with Rutherford category (Fig. 1.3). Even among patients
1 Peripheral Arterial Atherogenesis 7

a Death b Amputation
1.0 RF 1-3 1.0 RF 1-3
RF 4 RF 4
P < 0.001 P < 0.001
0.8 0.8
Cumulative risk

Cumulative risk
RF 5 RF 5
RF 6 RF 6
0.6 0.6

0.4 0.4

0.2 0.2

1 2 3 4 1 2 3 4
Years Years
RF 1-3 21,197 19,966 13,017 6,526 RF 1-3 21,197 19,649 12,719 6,304
RF 4 5,353 4,467 2,804 1,392 RF 4 5,353 4,237 2,609 1,267
RF 5 6,916 5,261 3,116 1,484 RF 5 6,916 4,125 2,289 1,046
RF 6 8,416 5,505 3,284 1,540 RF 6 8,416 2,457 1,395 614

c Death or Amputation d Myocardial infarction

1.0 RF 1-3 RF 5 0.12 RF 1-3
RF 4 RF 6 RF 4
0.10
0.8
Cumulative risk

Cumulative risk

RF 5
P < 0.001 0.08 RF 6
0.6
0.06
0.4
0.04
0.2 0.02 P < 0.001

1 2 3 4 1 2 3 4
Years Years
RF 1-3 21,197 19,649 12,719 6,304 RF 1-3 21,197 19,691 12,669 6,276
RF 4 5,353 4,237 2,609 1,267 RF 4 5,353 4,364 2,707 1,331
RF 5 6,916 4,125 2,289 1,046 RF 5 6,916 5,142 3,006 1,410
RF 6 8,416 2,457 1,395 614 RF 6 8,416 5,385 3,178 1,472

e Ischemic stroke
0.12
RF 1-3
0.10 RF 4
Cumulative risk

RF 5
0.08
RF 6
0.06

0.04
P < 0.001
0.02

1 2 3 4
Years
RF 1-3 21,197 19,700 12,687 6,277
RF 4 5,353 4,374 2,708 1,320
RF 5 6,916 5,143 2,997 1,403
RF 6 8,416 5,363 3,151 1,456

Fig. 1.3 Kaplan-Meier curves in a population with peripheral artery disease. The rate of death (a),
amputation (b), myocardial infarction (c), death or amputation (d), and ischemic stroke (e) gener-
ally increased with increasing Rutherford category, a measure of disease severity. The p value is a
log-rank test to determine differences between subgroups. (Figure from Reinecke [27])